Antipruritic agents and antipruritic compositions thereof

ABSTRACT

An antipruritic agent comprising a zinc-amino acid complex, and an antipruritic composition containing said antipruritic agent at a concentration of 2.6×10 -3  to 2.6×10 -1  M.

TECHNICAL FIELD

The present invention relates to an antipruritic agent and anantipruritic compound, and more specifically, it relates to anantipruritic agent and an antipruritic compound, in which zinc is themain ingredient.

BACKGROUND ART

The skin possesses the function of protecting the body from variousforms of stress due to the external environment, but if this bodymaintenance function becomes unbalanced, various forms of skinconditions appear, such as chapped skin and scabies.

As the majority of these skin conditions are accompanied by itching,this itching leads to skin pruritis, which can frequently exacerbate theoriginal skin condition.

There are individual differences in the degree of itching in such casesof pruritic skin diseases and cases of skin pruritis, ranging from thatwhich is extremely mild to that which is extremely severe. In addition,as a sebum deficiency, which is one cause of pruritis, is observed tosome degree in the case of elderly subjects, there are cases in whichurea ointment and zinc oxide ointment, etc. are used because of themoisture effects thereof.

Moreover, steroid preparations, anti-histamines and Crotamitonpreparations, etc., have been widely used in the past as antipruritics.

Nevertheless, itching accompanying liver and renal disfunction andmalignant tumors, metabolic disorders and senile pruritis, and pruriticskin diseases such as atopic dermatitis, eczema and urticaria, againstwhich these antipruritics are unable to demonstrate antipruriticeffects, are becoming a serious problem in the clinical setting.

As these diseases are frequently accompanied by serious itching, theparticular condition may be exacerbated due to scratch to the skinresulting from that itching. As such, an antipruritic able todemonstrate adequate antipruritic effects has been long awaited.Furthermore, steroid preparations, antihistamines, and so on may causeproblems due to adverse side effects, in certain cases.

DISCLOSURE OF THE INVENTION

Accordingly, the object of the present is to eliminate theabove-mentioned problems of the prior art by providing an antipruriticagent and antipruritic compound free of adverse side effects, actingdirectly on the itching itself, and being fast-acting.

In accordance with the present invention, there is provided anantipruritic comprising a zinc-amino acid complex.

In accordance with the present invention, there is also provided anantipruritic compound comprising an antipruritic agent comprised of azinc-amino acid complex at a concentration of 2.6×10⁻³ -2.6×10⁻¹ M(molar concentration, moles/liter), and a pharmacologically acceptablecarrier.

BEST MODE OF CARRYING OUT THE INVENTION

As a result of intensive research by the inventors of the presentinvention, to achieve the above-mentioned object, it was discovered thatan antipruritic agent having superior antipruritic properties andsuperior useability could be obtained by bonding zinc and an amino acidin a specific proportion, which led to the completion of the presentinvention.

Thus, it has been reported that itching receptors exist between theepidermis and dermis layers of the skin ("Modern Medicine", Vol. 16, No.11, pp. 46-47, 1987, Asahi Shimbunsha), and that the skin contains ahigh content of zinc, containing roughly 20% of the total amount of zincin the body, with particularly large amounts contained in the epidermis("Zinc and Clinical Medicine", Asakura Shoten, pp. 20-21, p. 123, 1984),indicating that there is an intimate relationship between the skin andzinc metabolism. In addition, a characteristic systemic skin rash occursin hereditary Acrodermatitis entheropathica, which is primarily causedby zinc deficiency, and a long-term implementation of high-calorieinfusions (venous feeding). The cause of this in the former case is aninsufficient absorption of zinc in the small intestine, while the causein the latter case is the chelation of zinc in the body by amino acidsand sugars contained in the infusion liquid resulting in transport andexcretion of zinc outside the body. It has also been reported that theseskin diseases are recovered by a replacement of zinc ("Zinc and ClinicalMedicine", Asakura Shoten, pp. 77-97, 1984). The inventors of thepresent invention thus conducted their research by focusing on therelationship between zinc and itching. As amino acids and sugars wereconsidered for use as carriers of zinc based on the results of researchinto zinc metabolism, a bound form of zinc and amino acid was used forthe form in which zinc is supplied to the body.

The following provides a detailed description of the constitution of thepresent invention.

The zinc and amino acid, the main ingredients, are known substances andmay be those which are commercially available.

The supply form of the zinc used in the present invention refers to zincmetal, its inorganic salts such as a sulfate, carbonate or nitratethereof, as well as its organic salts such as an acetate or oxalatethereof.

In addition, the amino acid referred to in the present invention refersto neutral, acidic and basic and all other amino acids as well as theirinorganic salts such as hydrochlorides thereof and their organic saltssuch as acetates thereof. Furthermore, neutral to acidic amino acids areparticularly preferable, as they enhance the antipruritic effects.

In the antipruritic agent of the present invention, the preferablebonding mole ratio of zinc to amino acid is 1:2. When the bondingprocedure is performed at a mole ratio of less than 1:2, adequateeffects corresponding to the amount of zinc will not be obtained. Inaddition, when the amino acid is blended in at a mole ratio in excess of1:2, no effects will be demonstrated due to the excess amount of aminoacid.

The amount of zinc-amino acid complex blended into the antipruriticcomposition of the present invention is generally 2.6×10⁻³ -2.6×10⁻¹ M,preferably 1.3×10⁻² -2-1.3×10⁻¹ M. When the amount of zinc-amino acidcomplex blended is too low, although the manufacturing of the drug iseasy, the antipruritic effects are inferior, thus making thisundesirable. Conversely, when the amount of zinc-amino acid complexblended is too high, it is necessary to use a large amount of glycerineand alcohol to dissolve the zinc-amino acid complex. This lowers thestability of the preparation and hinders the useability thereof, thusmaking this undesirable.

Furthermore, where the zinc-amino acid complex is less than 1.3×10⁻¹ M,since it is soluble in water and physiological saline, it can bedissolved as is, thus allowing it to be used for external application oras an injection drug. Where, however, the zinc-amino acid complexexceeds 13×10⁻¹ M, since it cannot be dissolved in water as is, it mustbe dissolved in glycerine, ethyl alcohol, glycol or water, etc.

The amount blended when blending glycerol into the antipruriticcomposition pertaining to the present invention is generally 5.0-60.0 wt%, preferably 10.0-50.0 wt %.

When the amount of glycerine blended is too low, it is not possible todissolve the zinc-amino acid complex, thus making this undesirable.Conversely, when the amount of glycerine is too high, the useability ofthe composition is remarkably hindered, thus also making thisundesirable.

A poly-glycerol such as di-glycerol can be used alone or in combinationwith glycerol, to dissolve the zinc-amino acid complex in place ofglycerol.

The blended amount when blending ethyl alcohol into the antipruriticcomposition pertaining to the present invention is 3.0-50.0 wt %,preferably 5.0-40.0 wt %.

When the amount of ethyl alcohol blended is too low, it is not possibleto dissolve the zinc, etc., thus making this undesirable.

Conversely, when the amount blended is too high, there is an increase inthe degree of skin irritation, thus also making this undesirable.

Isopropyl alcohol or acetone, etc., also can be used to dissolve thezinc, etc., in place of ethyl alcohol, but ethyl alcohol is preferablein terms of solubility.

Examples of the glycol blended into the antipruritic compositionpertaining to the present invention include propylene glycol,dipropylene glycol, 1,3-butylene glycol, hexylene glycol andpolyethylene glycol. These glycols are blended in to function asassistants in dissolving the zinc-amino acid complex, and the amountblended is 0.5-30.0 wt %, preferably 5.0-20.0 wt %.

When the amount of glycol blended is too low, a large amount of glyceroland ethyl alcohol must be blended in order to dissolve the zinc-aminoacid complex, and conversely, when the amount blended is too high, itwill not be possible to dissolve the zinc-amino acid complex, thusmaking both cases undesirable.

In addition, the amount of water blended into the antipruritic compoundpertaining to the present invention is generally 5.0-50.0 wt %,preferably 10.0-40.0 wt %.

As the zinc-amino acid complex most likely exists in the form of acomplex, its solubility is extremely specific, and its stability isgreatly affected by the pH thereof.

The antipruritic composition according to the present invention ismaintained stable for a long time by adjusting same to a pH of 2.0-10.0,preferably 4.0-8.0.

In order to prepare an antipruritic composition in accordance with thepresent invention, antioxidants, preservatives, buffers, polar oils,surface activators, water-soluble polymers and other drugs can beblended as desired, in addition to the above-mentioned requiredingredients.

Furthermore, as previously described, although glycerol, ethyl alcohol,glycol and water are required to dissolve a zinc-amino acid complex,etc., in excess of 1.3×10⁻¹ M, where the amount of zinc-amino acidcomplex is less than 1.3×10⁻¹ M, a combination of the abovementionedingredients is not always necessary.

In addition, the present invention is able to be applied inpharmaceutical or non-pharmaceutical products, as well as in cosmeticsand drinks, and so on.

When using the antipruritic agent according to the present invention asa antipruritic composition for external application on the skin, theamount of zinc-amino acid complex is generally made to be 2.6×10⁻³-2.6×10⁻¹ M, preferably 1.3×10⁻² -1.3×10⁻¹ M.

Furthermore, when using the external use composition according to thepresent invention as a preparation for external application on the skin,those ingredients that are normally blended into ordinary externalpreparations for application on the skin, such as oils, water, surfaceactivators, moisture retention agents, lower alcohols, thickeners,chelating agents, dyes, preservatives and perfumes, may be suitablyblended.

In addition, external preparations for application on the skin broadlyrefer to those preparations used on the skin, and examples includeexternal use medications such as ointments as well as facial cosmeticproducts such as a skin wash, milky lotions and cremes.

Moreover, the external use composition according to the presentinvention also can be used on the head. Examples of these applicationsinclude hair tonic, milky lotions for the scalp, hair liquid, hairshampoo, hair rinse, hair cream, and hair spray.

When used as a composition for external use on the head, oilyingredients, UV absorbers, preservatives, moisture retention agents,surface activators, perfumes, water, alcohol, thickeners, coloringagents, medicinal drugs, and so on can be blended in.

When using the antipruritic agent according to the present invention asan internal medicine or injection, those ingredients which are normallyblended in general internal medicines and injections can be suitablyblended in as necessary. Examples of such ingredients include vehiclessuch as cornstarch, lactose, glucose and crystal cellulose; binders suchas starch, gelatin and acacia; decomposing agents such as agar, sodiumcarboxycellulose and sodium hydrogencarbonate; lubricating agents suchas magnesium stearate and talc,; isotonic agents such as sodiumchloride; buffers such as phosphate and borate; and, other additives,dissolving assistants, stabilizers and preservatives.

In addition, examples of the forms of these internal medicines includepharmaceuticals as well as powders, grains, granules, pills, tablets,capsules, internally consumed liquids and drinks in health foods, andbeverages and so on.

EXAMPLES

The following provides an explanation of suitable Examples of thepresent invention, but it is understood that the present invention isnot limited to these Examples. Furthermore, unless specified otherwise,the zinc and amino acid amounts are indicated in molar concentrations.

First, the manufacturing process of the antipruritic agent according tothe present invention will be explained.

Example 1 Zinc-Glycine Complex (H₂ N--CH₂ --COO)₂ Zn

While stirring at 60° C. after dissolving 1.65 g of glycine(commercially available product) in water, a solution of 2.37 g of zincacetate dihydrate dissolved in 6 ml of water was dropwise added thereto.Stirring was performed for 30 minutes at the same temperature, afterwhich the solution was allowed to stand overnight in a refrigerator. Theprecipitated solid was recovered by filtration and recrystallized with amixture of ethanol and water to obtain 3.52 g of crystal.

M.P.: >270° C.

IR.sub.(KBr) : 3350, 1640 cm⁻¹

Elementary analysis values: C₄ H₈ N₂ O₄ Zn.H₂ O

Calculated values: C 8.97, H 1.88, N 5.23

Analytical values: C 8.88, H 1.75, N 5.18

Example 2 Zinc-Aspartic Acid Complex ##STR1##

L-aspartic acid (2.00 g, 15.0 mmol) was added to an MeOH solution ofNaOMe (prepared with Na: 0.69 g, MeOH: 50 ml) at 0° C. and stirred. AnMeOH solution (30 ml) of zinc acetate dihydrate (3.30 g) was thengradually dropwise added thereto at room temperature. After stirring for2 hours at that same temperature, the precipitated crystal (insuspension) was recovered by filtration, washed with water, air dried,and then dried under a reduced pressure (5 mmHg, 80° C.).

Yield: 1.65 g

M.P.: >270° C.

IR.sub.(KBr) : 3300, 1640, 1630 cm⁻¹

Elementary analysis values: C₈ H₁₂ N₂ O₈ Zn.H₂ O

Calculated values: C 27.64, H 4.06, N 8.06

Analytical values: C 27.88, H 4.10, N 7.90

Example 3 Zinc-Glutamic Acid Complex ##STR2##

L-glutamic acid (2.0 g, 13.6 mmol) was added to an MeOH solution ofNaOMe (prepared with Na: 0.31 g, MeOH: 50 ml) at 0° C. and stirred. AnMeOH solution (30 ml) of zinc acetate dihydrate (1.49 g) was then slowlydropwise added thereto. After refluxing and stirring for 5 hours, theprecipitated crystal (in suspension) was recovered by filtration, washedwith water, air dried, and then dried under a reduced pressure (5 mmHg,80° C.).

Yield: 1.40 g

M.P.: >270° C.

IRr.sub.(KBr) : 3400, 1645, 1640 cm⁻¹

Elementary analysis values: C₁₀ H₆ N_(2n) O₈ Zn.2H₂ O

Calculated values: C 30.51, H 5.12, N 7.12

Analytical values: C 30.79, H 4.92, N 7.35

Example 4 Zinc-Valine Complex ##STR3##

L-valine (2.00 g, 17.1 mmol) was added to an MeOH solution of NaOMe(prepared with Na: 0.39 g, MeOH: 50 ml) at 0° C. and stirred. An MeOHsolution (30 ml) of zinc acetate dihydrate (1.90 g) was then slowlydropwise added thereto at room temperature. After stirring for 6 hoursat that same temperature, the precipitated crystal (in suspension)recovered by filtration, washed with water, air dried, and then driedunder a reduced pressure (5 mmHg, 80° C.).

Yield: 0.40 g

M.P.: >270° C.

IR.sub.(KBr) : 3400, 1640 cm⁻¹

Elementary analysis values: C₁₀ H₂₀ N₂ O₄ Zn.3/2H₂ O

Calculated values: C 36.99, H 7.14, N 8.68

Analytical values: C 37.13, H 6.92, N 8.46

Example 5 Zinc-Isoleucine Complex ##STR4##

L-isoleucine (2.00 g, 15.3 mmol) was added to an MeOH solution of NaOMe(prepared with Na: 0.35 g, MeOH: 50 ml) at 0° C. and stirred. An MeOHsolution (30 ml) of zinc acetate dihydrate (1.67 g) was then slowlydropwise added thereto at room temperature. After stirring for hours atthe same temperature, the solution was concentrated to half its originalvolume, followed by the addition of an equal volume of water. Theprecipitated crystal was recovered by filtration, air dried, and thendried under a reduced pressure (5 mmHg, 80° C.).

Yield: 1.03 g

M.P.: >270° C.

IR.sub.(KBr) : 3350, 1635 cm⁻¹

Elementary analysis values: C₁₂ H₂₄ N₂ O₄ Zn.1/2H₂ O

Calculated values: C 43.06, H 7.53, N 8.37

Analytical values: C 43.15, H 7.42, N 8.36

Example 6 Zinc-Histidine Complex ##STR5##

L-histidine (2.00 g, 12.8 mmol) was added to an MeOH solution of NaOMe(prepared with Na: 0.30 g, MeOH: 50 ml) at 0° C. and stirred. An MeOHsolution (30 ml) of zinc acetate dihydrate (1.41 g) was then slowlydropwise added thereto at room temperature. After stirring for 3 hours,the precipitated crystal (in suspension) was recovered by filtration,washed with water, air dried, and then concentrated under a reducedpressure (5 mmHg, 80° C.).

Yield: 0.40 g

M.P.: >285° C.

IR.sub.(KBr) : 3310, 1640 cm⁻¹

Elementary analysis values: C₁₂ H₁₆ N₆ O₄ Zn.3/2H₂ O

Calculated values: C 35.97, H 4.78, N 20.97

Analytical values: C 36.21, H 4.58, N 20.75

Example 7 Zinc-Phenylalanine Complex ##STR6##

L-phenylalanine (2.00 g, 12.1 mmol) was added to an MeOH solution ofNaOMe (prepared with Na: 0.30 g, MeOH: 50 ml) at 0° C. and stirred. AnMeOH solution (30 ml) of zinc acetate dihydrate (1.30 g) was then slowlydropwise added thereto at room temperature. After stirring for 3 hours,the precipitated crystal (in suspension) was recovered by filtration,washed with water, air dried, and then dried under a reduced pressure (5mmHg, 80° C.).

Yield: 2.06 g

M.P.: >270° C.

IR.sub.(KBr) : 3300, 1640 cm⁻¹

Elementary analysis values: C₁₈ H₂₀ N₂ O₄ Zn.H₂ O

Calculated values: C 54.91, H 5.12, N 7.11

Analytical values: C 54.73, H 5.13, N 7.00

Example 8 Zinc-Methionine Complex ##STR7##

L-methionine (2.00 g, 13.4 mmol) was added to an MeOH solution of NaOMe(prepared with Na: 0.30 g, MeOH: 50 ml) at 0° C. and stirred. An MeOHsolution (30 ml) of zinc acetate dihydrate (1.50 g) was then slowlydropwise added thereto at room temperature. After stirring for 3 hours,the precipitated crystal (in suspension) was recovered by filtration,washed with water, air dried, and then dried under a reduced pressure (5mmHg, 80° C.).

Yield: 2.13 g

M.P.: >270° C.

IR.sub.(KBr) : 3310, 1640 cm⁻¹

Elementary analysis values: C₁₈ H₂₀ N₂ O₄ Zn.3/2H₂ O

Calculated values: C 33.20, H 5.57, N 7.74

Analytical values: C 33.12, H 5.70, N 7.66

Example 9 Zinc-Leucine Complex ##STR8##

L-Leucine (2.00 g, 15.3 mmol) was added to an MeOH solution of NaOMe(prepared with Na: 0.36 g, MeOH: 50 ml) at 0° C. and stirred. An MeOHsolution (30 ml) of zinc acetate dihydrate (1.67 g) was then slowlydropwise added thereto at room temperature. After stirring for 2 hoursat that same temperature, the solution was concentrated to half itsoriginal volume, followed by the addition of an equal volume of water.The precipitated crystal was recovered by filtration, air dried, andthen dried under a reduced pressure (5 mmHg, 80° C.).

Yield: 2.00 g

M.P.: >270° C.

IR.sub.(KBr) : 3350, 1635 cm⁻¹

Elementary analysis values: C₁₂ H₂₄ N₂ O₄ Zn.1/2H₂ O

Calculated values: C 43.06, H 7.53, N 8.37

Analytical values: C 43.29, H 7.34, N 8.29

The antipruritic effects of the zinc-amino acid complex according to thepresent invention were examined as follows.

Antipruritic Effects Test

Although the primary cause of itching is believed to be mainly relatedto histamine, there are many cases of itching which cannot be suppressedwith anti-histamines, and these cases create serious problems in theclinical setting.

As such, prurigenic animal models were prepared in which itching cannotbe suppressed by anti-histamines, by intracutaneously administeringeither bradykinin or kallikrein to guinea pigs, in order to confirm theantipruritic effects of the antipruritic agent according to the presentinvention.

(1) Antipruritic Effects Against Itching Induced by Bradykinin inPrurigenic Animals

The prurigenic substance, bradykinin, was intracutaneously administeredto the flanks of healthy Hartley male guinea pigs to obtain theprurigenic animals.

The itching behavior was then evaluated following the evaluationstandards indicated below, expressed in the form of itching activity.

    ______________________________________                                        Evaluation Method           Score                                             ______________________________________                                        (1) Stressful behavior due to itching                                                                         1                                                 When the animal demonstrated the following                                    forms of behavior not normally observed:                                      *Scratching of the face, ears, etc., with forepaw                             *Trembling of the body                                                        *Biting the floor or paws                                                     *Firmly standing on back legs                                             (2) Scratching of the prurigenic site on the                                                                  2                                                 flank with the mouth or back legs                                         (3) Continuously repeating the behavior of (2)                                                                3                                                 above three or more times                                                 ______________________________________                                    

The above behavioral observations were performed simultaneously by threesubjects or more for 20 minutes for each group of animals. The itchingactivity was scored and the mean value was then determined. These meanvalues were then indicated as antipruritic effects, taking the itchingactivity of a vehicle control group to be 100%.

The hair of the right flanks of healthy male guinea pigs (body weight:450-600 g) was shaven using an electric shaver on the previous day, andthereafter the animals were grouped into groups of five animals each.Each of the groups were intracutaneously administered with 50 μg/0.05 mlof bradykinin into the right flank. After five minutes had elapsed, anexternally applied vehicle was applied to one of the groups (controlgroup)(composition: glycerine 40%, ethanol 25%, and water 35%). For theother groups, 0.1 ml of each sample containing the test substance ateach concentration was externally applied to the site of intracutaneousadministration of bradykinin. The itching behavior was then observed for20 minutes, to determine the itching activity score.

A study was thus conducted regarding the type of amino acid andantipruritic effects based on the evaluation method described above. Theresults are indicated in Table 1.

                  TABLE 1                                                         ______________________________________                                        Relationship Between Amino Acid                                               and Itching Activity (n = 5)                                                                                        Itching                                 Amino                                 Activity                                Acid    Conc.      Zinc      Conc.    (%)                                     ______________________________________                                        Vehicle --         --        --       100.0                                   control                                                                       Glycine 2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  67.5                                    Serine  2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  73.0                                    Cysteine                                                                              2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  70.8                                    Leucine 2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  82.3                                    Methionine                                                                            2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  70.5                                    Tyrosine                                                                              2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  70.5                                    Tryptophan                                                                            2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  72.6                                    Glutamic                                                                              2 × 10.sup.-2  M                                                                   Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  62.9                                    acid                                                                          Histidine                                                                             2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  90.0                                    Arginine                                                                              2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  93.4                                    Lysine  2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  94.3                                    ______________________________________                                    

As is clear from Table 1, although a decrease in itching activity isobserved for all zinc-amino acid complexes, particularly favorableantipruritic effects are observed for complexes of zinc and neutral toacidic amino acids.

The relationship between the bonding ratio of the zinc-amino acidcomplex and itching activity was examined as follows.

More specifically, the itching activity was examined by sequentiallyvarying the amount of amino acid added with respect to a constant amountof zinc during the bonding reaction. The results are indicated in Table2.

                  TABLE 2                                                         ______________________________________                                        Effects of the Antipruritic Agent of the Present Invention                    on Itching Caused by Bradykinin (n = 5)                                                                             Itching                                 Amino                                 Activity                                Acid    Conc.      Zinc      Conc.    (%)                                     ______________________________________                                        Vehicle --         --        --       100.0                                   control                                                                       Control --         Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  98.0                                    Glycine 0.5 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  96.7                                    Glycine 1.0 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  94.0                                    Glycine 1.5 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  93.5                                    Glycine 2.0 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  68.3                                    Glycine 4.0 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  71.1                                    Tryptophan                                                                            0.5 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  96.8                                    Tryptophan                                                                            1.0 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  95.7                                    Tryptophan                                                                            1.5 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  95.0                                    Tryptophan                                                                            2.0 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  67.9                                    Tryptophan                                                                            4.0 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  69.0                                    Glutamic                                                                              0.5 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  95.7                                    acid                                                                          Glutamic                                                                              1.0 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  92.1                                    acid                                                                          Glutamic                                                                              1.5 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  91.1                                    acid                                                                          Glutamic                                                                              2.0 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  61.8                                    acid                                                                          Glutamic                                                                              4.0 × 10.sup.-2 M                                                                  Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  75.5                                    acid                                                                          ______________________________________                                    

As is clear from Table 2 above, the zinc-amino acid complex demonstratesfavorable antipruritic effects at a mole ratio of 1:2, but theantipruritic effects per unit amount of zinc decrease if the amount ofzinc is increased beyond that ratio. Similarly, the antipruritic effectsper unit amount of zinc do not improve when the amount of amino acid isalso increased beyond that ratio.

Thus, it is suggested that zinc and amino acid form a special bound format a mole ratio of 1:2 that demonstrates superior antipruritic effects.

This is believed to be probably due to the zinc and amino acid forming acomplex in the ratio of 1:2.

(2) Antipruritic Effects Against Itching Induced by Kallikrein inPrurigenic Animals

Kallikrein is another known physiological prurigenic substance whichcauses itching that cannot be suppressed with anti-histamines(International Journal of Dermatology, Vol. 14, pp. 456-484, 1975).

As such, prurigenic animals in which itching cannot be suppressed withanti-histamines were prepared by intracutaneously administeringkallikrein to guinea pigs, in order to confirm the antipruritic effectsof the antipruritic agent according to the present invention.

Furthermore, the evaluation method used was the same as that previouslydescribed.

The hair of the right flanks of healthy male guinea pigs (body weight:450-600 g) was shaven using an electric shaver on the previous day, andthereafter, the animals were grouped into groups of five animals each.Each of the groups were intracutaneously administered with 25 units/0.05ml of kallikrein into the right flank. After five minutes had elapsed,an externally applied vehicle was applied to one of the groups (controlgroup). For the other groups, 0.1 ml of each mixed compound of zinc andamino acid at each concentration was externally applied to the site ofintracutaneous administration of kallikrein. The itching behavior wasthen observed for 20 minutes, to determine the itching activity score.

The test was thus carried out regarding the type of amino acid andantipruritic effects, based on the evaluation method described above.The results are indicated in Table 3.

                  TABLE 3                                                         ______________________________________                                        Effects of the Antipruritic Agent of the Present Invention                    on Itching Caused by Kallikrein (n = 5)                                                                             Itching                                 Amino                                 Activity                                Acid    Conc.      Zinc      Conc.    (%)                                     ______________________________________                                        Vehicle --         --        --       100.0                                   control                                                                       Glycine 2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  72.3                                    Tryptophan                                                                            2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  78.0                                    Glutamic                                                                              2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  67.1                                    acid                                                                          Histidine                                                                             2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  93.3                                    Arginine                                                                              2 × 10.sup.-2 M                                                                    Zinc sulfate                                                                            1 × 10.sup.-2 M                                                                  98.5                                    ______________________________________                                    

As is clear from Table 3 above, the antipruritic effects with respect toitching caused by kallikrein are excellent in the case of acidic toneutral amino acids such as glycine and glutamic acid.

                  TABLE 4                                                         ______________________________________                                        Effects of the Antipruritic Agent of the Present Invention on                 Itching Caused by Kallikrein (n = 5)                                                                                Itching                                 Amino                                 Activity                                Acid    Conc.       Zinc     Conc.    (%)                                     ______________________________________                                        Vehicle --          --       --       100.0                                   control                                                                       Control --          Zinc     1 × 10.sup.-2 M                                                                  101.3                                                       sulfate                                                   Glycine 0.25 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  101.0                                                       sulfate                                                   Glycine  0.5 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  100.9                                                       sulfate                                                   Glycine  1.0 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  100.9                                                       sulfate                                                   Glycine  1.5 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  99.9                                                        sulfate                                                   Glycine  2.0 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  71.3                                                        sulfate                                                   Glycine  4.0 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  70.8                                                        sulfate                                                   Glutamic                                                                              0.25 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  99.6                                    acid                sulfate                                                   Glutamic                                                                               0.5 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  99.0                                    acid                sulfate                                                   Glutamic                                                                               1.0 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  98.8                                    acid                sulfate                                                   Glutamic                                                                               1.5 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  98.1                                    acid                sulfate                                                   Glutamic                                                                               2.0 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  67.5                                    acid                sulfate                                                   Glutamic                                                                               4.0 × 10.sup.-2 M                                                                  Zinc     1 × 10.sup.-2 M                                                                  72.4                                    acid                sulfate                                                   ______________________________________                                    

According to Table 4, excellent effects against itching caused bykallikrein were also observed for bound forms having a zinc to aminoacid ratio of 1:2.

As indicated above, it was confirmed that the antipruritic agent of thepresent invention can be a new antipruritic agent having an effectagainst itching that cannot be suppressed with conventionalanti-histamines and so on.

(3) Effects Due to Formation of a Complex

Next, the inventors of the present invention compiled the followingexperimental system, in order to confirm whether the antipruriticeffects of the present invention were due to the blending ratio of thezinc and amino acid, or due to the formation of a bound form (complex).

In Table 5 shown below, in the case of an amino acid alone, the aminoacid was dissolved to a concentration of 1×10⁻² M. In the case of thezinc sulfate-amino acid mixture groups, the zinc sulfate was dissolvedto a concentration of 1×10⁻² M and the amino acid was dissolved to aconcentration of 2×10⁻² M. In the case of a zinc-amino acid complex, thecomplex was dissolved to a concentration of 1×10⁻² M. In each case,water was used for the solvent. These solutions were then used as thetest samples.

The bound substances (precipitates) formed in the above-mentionedExamples 1-9 are considered to be complexes, and stirring is requiredover an extended period of time in order to obtain the bound substances.Consequently, even if the zinc sulfate and amino acid were simplydissolved in solvent (zinc sulfate-amino acid mixture groups), the boundform (complex) essentially would not be formed.

                  TABLE 5                                                         ______________________________________                                                                   n = 5                                                              Itching Activity                                                              Bradykinin                                                                            Kallikrein                                            ______________________________________                                        Vehicle control group                                                                           100       100                                               Glutamic acid alone                                                                             101       102                                               Zinc sulfate-glutamic acid                                                                       87        90                                               mixture group                                                                 Zinc-glutamic acid complex                                                                       65        67                                               Vehicle control group                                                                           100       100                                               Aspartic acid alone                                                                             101       101                                               Zinc sulfate-aspartic acid                                                                       91        91                                               mixture group                                                                 Zinc-aspartic acid complex                                                                       70        69                                               Vehicle control group                                                                           100       100                                               Glycine alone      98        99                                               Zinc sulfate-glycine                                                                             88        92                                               mixture group                                                                 Zinc-glycine complex                                                                             73        75                                               ______________________________________                                    

According to Table 5 above, the antipruritic agent according to thepresent invention possesses remarkable effects as a complex, and inaddition, it is clear that it does not demonstrate antipruritic effectssimply as a result of the coexistence of zinc and amino acid.

The following provides an explanation of the antipruritic compositionwhich uses the antipruritic agent according to the present invention.

First, the composition of an external use antipruritic composition intowhich is blended the antipruritic agent according to the presentinvention, together with its pharmacological effects, are indicated inTable 6 below. Note, the blended amounts are indicated in wt %.

                  TABLE 6                                                         ______________________________________                                                                   n = 5                                                       Example                                                                              Example  Comp.     Comp.                                               10     11       Example 1 Example 2                                  ______________________________________                                        (1) Zinc-glycine                                                                             0.23     0.23   --      --                                         complex*.sup.1                                                            (2) Zinc sulfate*.sup.2                                                                      --       --     0.27    0.27                                   (3) Glycine    --       5.0    --      0.08                                   (4) Glycerol   20.0                                                           (5) Propylene  10.0                                                               glycol                                                                    (6) Ethyl alcohol                                                                            5.0                                                            (7) Hydroxypropyl                                                                            1.0                                                                cellulose                                                                 (8) Methylpara-                                                                              0.05                                                               benzene                                                                   (9) Purified water                                                                           Balance                                                                       Total 100.0%                                                   Itching Activity                                                                         Example  Example  Comp.   Comp.                                               10       11       Example 1                                                                             Example 2                                Bradykinin-induced                                                                       64       65       97      86                                       itching                                                                       Kallikrein-induced                                                                       66       68       94      89                                       itching                                                                       ______________________________________                                         *.sup.1 Monohydrate                                                           *.sup.2 Hexahydrate (each equivalent to roughly 1 × 10.sup.-2 M)   

Preparation Process

Ingredients (1) and (8) were added to ingredients (4) and (6), followedby heating to 40°-50° C. and stirring until dissolved. On the otherhand, ingredient (5) was wetted in advance with ingredient (7) followedby the addition of ingredients (2), (3) and (9). After stirring untildissolved, the compound dissolved above was added gradually and stirredto obtain the desired preparation.

This antipruritic composition was stable even after long-term storage attemperatures over a range of -5 to 40° C.

According to Table 6 above, the antipruritic compositions according toExample 10 and Example 11 possess a superior antipruritic activity. Inaddition, as is clear from Example 11, the presence of excess amino aciddoes not have an effect on antipruritic activity.

On the other hand, as described above, the zinc-amino acid complex isfirst formed by stirring for an extended time in the presence of bothzinc and amino acid. As indicated in Comparative Example 2, it isbelieved that simply blending zinc sulfate and glycine into the compoundessentially does not result in the formation of the bound substance(complex), due in part to the relationship thereof with otheringredients.

As a result, it was determined that, in order for the composition tosufficiently demonstrate antipruritic effects, preferably the zinc-aminoacid complex is formed in advance, after which said zinc-amino acidcomplex is added to each of the other ingredients.

Example 12 External Use Antipruritic Agent

    ______________________________________                                        (1) Zinc-serine complex                                                                            1.0 wt %                                                 (2) Isopropyl alcohol                                                                             25.0 wt %                                                 (3) Polyethylene glycol 300                                                                       20.0 wt %                                                 (4) Glycerol        20.0 wt %                                                 (5) Phosphate buffer                                                                              q.s.                                                      (6) Purified water  Balance                                                   ______________________________________                                    

Manufacturing Process

After adding ingredient (1) to ingredients (2) and (4), heating to atemperature of 40°-50° C. and stirring until dissolved, ingredient (3)was added followed by stirring and mixing. On the other hand, a solutionresulting from dissolving ingredient (5) in ingredient (6) by stirringwas added to the previously prepared liquid, followed by stirring, toobtain a stable preparation of pH=5.6.

This antipruritic was stable even when stored for an extended time at -5to 40° C. Moreover, the antipruritic effects were extremely high, asindicated in the abovementioned test of antipruritic properties.

Example 13 External Use Antipruritic Agent

    ______________________________________                                        (1) Zinc-cysteine complex                                                                          3.0 wt %                                                 (2) Glycerol        40.0 wt %                                                 (3) Ethyl alcohol   25.0 wt %                                                 (4) 1,3-butylene glycol                                                                           10.0 wt %                                                 (5) Isopropyl adipate                                                                              1.0 wt %                                                 (6) Hydroxymethyl cellulose                                                                        0.3 wt %                                                 (7) Purified water  Balance                                                   ______________________________________                                    

Preparation Process

Ingredient (1) was added to ingredients (2) and (3), and after heatingto a temperature of 40°-50° C. and stirring until dissolved, ingredients(4) and (5) were sequentially added, followed by stirring and mixing. Onthe other hand, after dissolving ingredient (6) in ingredient (7), thecomposition prepared above was added gradually, and sufficiently stirredto obtain a stable preparation of pH=5.50.

This antipruritic agent was stable even when stored for an extended timeat -5 to 40° C. Moreover, the antipruritic effects were extremely high,as indicated in the above-mentioned test of antipruritic properties.

Example 14 External Use Antipruritic Agent

    ______________________________________                                        (1) Zinc-leucine complex                                                                           5.0 wt %                                                 (2) Glycerol        45.0 wt %                                                 (3) Ethyl alcohol   30.0 wt %                                                 (4) Dipropylene glycol                                                                            10.0 wt %                                                 (5) Diethyl adipate  1.0 wt %                                                 (6) Purified water  Balance                                                   ______________________________________                                    

Preparation Process

To ingredient (1) was added ingredients (2) and (4), and after heatingto a temperature of 40°-50° C. and stirring until dissolved, ingredients(4), (5) and (6) were added sequentially, followed by stirring, toobtain a stable preparation of pH=5.2.

This antipruritic agent was stable even when stored for an extended timeat -5 to 40° C. Moreover, the antipruritic effects were extremely high,as indicated in the above-mentioned test of antipruritic properties.

Example 15 Sunburn Cream

    ______________________________________                                        (1)     Stearic acid      2.0 wt %                                            (2)     Cetanol           5.0 wt %                                            (3)     Hydrogenated oil  5.0 wt %                                            (4)     Silicone KF96A-6  5.0 wt %                                            (5)     Squalane         10.0 wt %                                            (6)     (POE).sub.40 stearyl ester                                                                      2.0 wt %                                            (7)     Glyceryl monostearate                                                                           3.0 wt %                                            (8)     Glycerol         10.0 wt %                                            (9)     Zinc-methionine complex                                                                         0.5 wt %                                            (10)    Antioxidant, preservative                                                                      q.s.                                                         and perfume                                                           (11)    Purified water   Balance                                              ______________________________________                                    

Preparation Process

Ingredients (1) through (7) and ingredient (10) were heated to dissolveat 70° C. to prepare the oil phase.

On the other hand, ingredient (9) was added to ingredients (3) and (11).After heating and stirring until dissolved, the oil phase was graduallyadded, followed by processing with a homogenizer and cooling.

This suntan cream was stable when stored for an extended time at -5 to40° C.

Example 16 Milky Lotion

    ______________________________________                                        (1)     Cetanol           0.5 wt %                                            (2)     Hydrogenated      1.0 wt %                                            (3)     Stearic acid      1.0 wt %                                            (4)     Squalane          3.0 wt %                                            (5)     (POE).sub.20 mol sorbitan                                                                       1.0 wt %                                                    monolaurate                                                           (6)     Glyceryl monostearate                                                                           1.0 wt %                                            (7)     Ethyl paraben    0.15 wt %                                            (8)     Perfume           0.2 wt %                                            (9)     Glycerol         10.0 wt %                                            (10)    Dipropylene glycol                                                                              5.0 wt %                                            (11)    Zinc-tyrosine complex                                                                           1.0 wt %                                            (12)    Carboxyvinyl polymer 105                                                                        0.3 wt %                                            (13)    Triethanol amine  1.0 wt %                                            (14)    Purified water   Balance                                              ______________________________________                                    

Preparation Process

Ingredients (1) through (8) were heated at 70° C. and stirred untildissolved, to prepare the oil phase. In addition, ingredient (11) wasdissolved in ingredients (9) and (10) and a portion of ingredient (14),to prepare the zinc-tyrosine complex phase. On the other hand,ingredient (13) was dissolved in the majority of ingredient (14) andheated to 70° C., to prepare the aqueous phase; this was then graduallyadded to the oil phase, followed by emulsion. After adding that in whichingredient (12) was dissolved in a portion of ingredient (14), thezinc-tyrosine complex phase was added, followed by processing with ahomogenizer, stirring, and cooling to obtain the milky lotion.

This milky lotion was stable even when stored for an extended time at -5to 40° C.

Example 17 Skin Wash

    ______________________________________                                        (1) Glycerol           5.0 wt %                                               (2) Denatured ethyl alcohol                                                                         15.0 wt %                                               (3) (POE).sub.60 hydrogenated castor oil                                                             1.0 wt %                                               (4) Zinc-tryptophan complex                                                                          0.3 wt %                                               (5) Perfume           q.s.                                                    (6) Methyl paraben     0.2 wt %                                               (7) Allantoin          0.1 wt %                                               (8) Purified water    Balance                                                 ______________________________________                                    

Preparation Process

Ingredients (1) through (6) were stirred until dissolved, at roomtemperature, to prepare the alcohol phase. In addition, after dissolvingingredient (7) in ingredient (8), the alcohol phase was gradually addedwhile stirring, to form a uniform solution to obtain a skin wash.

This skin wash was stable when stored for an extended time at -5 to 40°C. and moreover, possessed skin conditioning effects.

Example 18 Sunburn Ointment

    ______________________________________                                        (1)  Zinc-glutamic acid complex                                                                              2.5 wt %                                       (2)  Glycerol                 35.0 wt %                                       (3)  Polyethylene glycol (PEG-400)                                                                          25.0 wt %                                       (4)  Polyethylene glycol (PEG-6000)                                                                          5.0 wt %                                       (5)  Hydrogenated oil         12.0 wt %                                       (6)  Stearic acid              2.0 wt %                                       (7)  Isopropyl palmitate       2.0 wt %                                       (8)  Glyceryl monostearate     3.0 wt %                                       (9)  Methyl paraben            0.2 wt %                                       (10) Potassium hydroxide       0.1 wt %                                       (11) Purified water           13.2 wt %                                       ______________________________________                                    

Preparation Process

Ingredients (1) through (4) and a portion of ingredient (11) were addedand stirred at 70° C. until dissolved, to prepare the zinc-glutamic acidcomplex phase. On the other hand, ingredients (5) through (9) wereheated to 70° C. to prepare the oil phase. Ingredient (10) was added toingredient (11), followed by heating until dissolved, into which wasthen added the above oil phase. Finally, the previously preparedzinc-glutamic acid complex phase was added. After creating a uniformmixture with a homogenizer, the mixture was stirred and cooled to obtainthe sunburn ointment.

This ointment was stable when stored for an extended time at -5 to 40°C.

Example 19 Emulsion Ointment

    ______________________________________                                        (1)  Diglycerol isostearate    2.0 wt %                                       (2)  Water-swelling clay mineral (hectrite)*.sup.1                                                           1.5 wt %                                       (3)  Benzyldimethylstearylammonium chloride                                                                  0.5 wt %                                       (4)  Dimethyl polysiloxane     5.0 wt %                                       (5)  Liquid paraffin          18.8 wt %                                       (6)  Microcrystalline wax      2.0 wt %                                       (7)  Ethyl paraben             0.2 wt %                                       (8)  Deionized water          10.0 wt %                                       (9)  Glycerol                 48.0 wt %                                       (10) Propylene glycol         10.0 wt %                                       (11) Zinc-histidine complex    2.0 wt %                                       ______________________________________                                    

Preparation Process

After sufficiently allowing ingredient (2) to swell inside ingredient(8), it was dispersed in a solution in which ingredients (9), (10) and(11) were heated and dissolved in advance, to form the aqueous phase.

On the other hand, oil-soluble ingredients (1) and (3) through (7) weremixed and dissolved at roughly 0° C. to obtain the oil phase When theabove aqueous phase was gradually added while stirring the oil phasewith a stirring rod, an emulsified dispersion system was obtained. Thiswas then cooled to room temperature to obtain the desired emulsionointment.

This emulsion ointment was stable when stored for an extended time at -5to 40° C., and possessed skin conditioning effects.

Furthermore, the water-swelling clay mineral used 1 in this Example is atype of colloidal hydrate aluminum silicate having a three layerstructure, and is generally expressed with the general formula indicatedbelow:

    (X,Y).sup.2-3 (Si,Al).sub.4 O.sub.10 (OH).sub.2 Z.sub.1/3.nH.sub.2 O

where,

X=Al,Fe_(III),Mn_(III),Cr_(III)

Y=Mg,Fe,Ni_(II),Zn,Li

Z=K,Na,Ca

More specifically, this is comprised of natural or synthetic (in thiscase, the (OH) group in the formula is substituted with fluorine)members of the montmorillonite group such as montmorillonite, saponiteand hectrite.

Example 20 Hair Tonic

    ______________________________________                                        (1) Denatured ethyl alcohol                                                                         65.0 wt %                                               (2) Propylene glycol   5.0 wt %                                               (3) Glycerol           5.0 wt %                                               (4) Zinc-arginine complex                                                                            0.5 wt %                                               (5) Perfume           q.s.                                                    (6) (POE).sub.60 hydrogenated castor oil                                                             1.0 wt %                                               (7) Hinokitiol        0.01 wt %                                               (8) Vitamin E acetate  0.1 wt %                                               (9) Purified water    Balance                                                 ______________________________________                                    

Manufacturing Process

After heating and dissolving ingredient (4) in ingredients (1), (2) and(3), ingredients (5), (6) and (7) were added followed by stirring untildissolved. Moreover, ingredient (9) was added gradually while stirringto obtain the hair tonic.

This hair tonic was stable when stored for an extended time at -5 to 40°C.

Example 21 Tablet

100 mg of lactose, 30 mg of cornstarch, 80 mg of talc and 2 mg ofmagnesium stearate were added and mixed with 100 mg of zinc-lysinecomplex and formed into tablets.

In the case of an enteric coated preparation, the above-mentioned tabletwas coated with an enteric coating of hydroxypropylmethyl cellulosephthalate to obtain the enteric coated tablet.

This tablet was stable when stored for an extended time at -5 to 40° C.

Example 22 Capsule

150 mg of lactose, 100 mg of cornstarch and 1 mg of light-gravitysilicic anhydride were added and mixed with 50 mg of zinc-glysinecomplex and filled into a No. 2 gelatin hard capsule. In the case of anenteric coated capsule, the above-mentioned capsule was coated with anenteric coating of hydroxypropylmethyl cellulose phthalate to obtain theenteric coated capsule. This capsule was stable when stored for anextended time at -5 to 40° C.

Example 23 Injection Preparation

Zinc-serine complex was dissolved in Japanese Pharmacopoeiaphysiological saline in the proportion of 10 mg of complex to 10 ml ofsaline. This solution was then filtered through a sterile membranefilter. After dividing the filtrate among sterilized ampules, theampules were sealed.

This injection preparation was stable when stored for an extended timeat -5 to 40° C.

Industrial Applicability

According to the antipruritic agent or antipruritic composition of thepresent invention containing a zinc-amino acid complex, it is able todemonstrate superior antipruritic effects even with respect to itchingfor which sufficient antipruritic effects were unable to be obtainedwith conventional antipruritic agents or antipruritic compositions.

We claim:
 1. An antipruritic agent comprising a zinc-amino acid complex of a naturally occurring α-amino acid.
 2. An antipruritic agent as claimed in claim 1, wherein the bonding mole ratio of zinc-amino acid of the above-mentioned zinc-amino acid complex is 1:2.
 3. An antipruritic agent as claimed in claim 1, wherein the α-amino acid is at least one compound selected from the group consisting of acidic α-amino acids and neutral α-amino acids.
 4. An antipruritic compositions comprising the antipruritic agent described in claim 1 at a concentration of 2.6×10⁻³ to 2.6×10⁻¹ M, and a pharmacologically acceptable carrier.
 5. An antipruritic agent as claimed in claim 2, wherein the α-amino acid is at least one compound selected from the group consisting of acidic α-amino acids and neutral α-amino acids.
 6. An antipruritic composition comprising the antipruritic agent described in claim 2 at a concentration of 2.6×10⁻³ to 2.6×10⁻¹ M, and a pharmacologically acceptable carrier.
 7. An antipruritic composition comprising the antipruritic agent described in claim 3 at a concentration of 2.6×10⁻³ to 2.6×10⁻¹ M, and a pharmacologically acceptable carrier.
 8. An antipruritic composition comprising the antipruritic agent described in claim 5 at a concentration of 2.6×10⁻³ to 2.6×10⁻¹ M, and a pharmacologically acceptable carrier.
 9. An antipruritic agent comprising a zinc-glutamic acid complex having the following formula: ##STR9## 